Mechanism of drug resistance identified in human lung adenocarcinoma cell line SPC-A1 selected for resistance to docetaxel

Objective  To investigate the mechanism of resistance to docetaxel in human lung cancer. Methods  Human lung carcinoma SPC-A1/Docetaxel cells were derived from parental SPC-A1 cells by continuous exposure to increasing concentration of docetaxel. The drug sensitivity was measured by MTT assay in vitro. The cDNA microarray identified a set of differentially expressed genes, and some genes were confirmed by RT-PCR. P-glycoprotein level was measured by flow cytometry analysis. Results  The results of drug sensitivity measured by MTT assay showed that SPC-A1/Docetaxel cells were 13.2-fold resistant to docetaxel and cross-resistant at varying levels to other drugs. The cDNA microarray results identified a set of differentially expressed genes, which showed 428 genes that were up-regulated and 506 genes that were down-regulated in SPC-A1/Docetaxel cells, and some genes were confirmed by RT-PCR. Flow cytometry analysis suggests expression of P-glycoprotein (P-gp) was more abundant in SPC-A1/Docetaxel cells than in the parental cells and docetaxel selection reduces the apoptotic response. Conclusion  The results suggest that docetaxel selection led to changes in gene expression that contribute to the multidrug resistance phenotype. This work was supported by a grant from the Postdoctor Research Project of Jiangsu Province (No.0602031B)     

表柔比星联合多西他赛或紫杉醇治疗乳腺癌效果差异分析

目的探讨表柔比星联合多西他赛或紫杉醇治疗乳腺癌的效果差异。方法选取2018年2月至2019年7月本院收治的86例乳腺癌患者,根据动态随机分组法将其分为对照组(n=43)和观察组(n=43),对照组采用表柔比星联合紫杉醇治疗,观察组采用表柔比星联合多西他赛治疗,比较两组临床缓解率、1年内复发率、生存时间以及不良反应发生率。结果两组患者临床缓解率差异经统计学软件检验显示无统计学意义(P>0.05);观察组1年内复发率和不良反应发生率低于对照组,生存时间长于对照组,差异经统计学软件检验显示有统计学意义(P<0.05)。结论表柔比星联合多西他赛或紫杉醇对乳腺癌的治疗效果相近,但联合多西他赛的不良反应风险更低,还可延长患者生存时间。     

多西紫杉醇作为晚期非小细胞肺癌的二线治疗药物的系统评价

目的系统评价多西紫杉醇作为晚期非小细胞肺癌二线治疗药物的疗效、不良反应、生存质量及给药方案。方法电子检索Medline（1991～2008．2）、Pubmed、CBMDisc等数据库，对符合纳入标准的研究，采用RevMan4．2软件进行Meta分析。结果共有8篇文献纳入研究。多西紫杉醇治疗晚期非小细胞肺癌疗效与支持性疗法相比，疾病进展期和中位生存期明显延长，分别是10．6周和6．7周（P〈0．001）、7．0月和4．6月（P〈0．001），1年生存率分别为37％和11％。不良反应研究中，3—4级血液学不良反应在多西紫杉醇组中发生率较高，其中高剂量组（100mg／m^2）发生率高于低剂量组（75mg／m^2）；3～4级非血液学不良反应，多西紫杉醇组和支持治疗组发生率相似。另外以长春瑞滨或异环磷酰胺为对照的研究显示，多西紫杉醇组反应率、疾病进展时间和生存率优于对照；4级血液学不良反应多西紫杉醇组高于对照组，其他3～4级非血液学不良反应的发生率无明显规律。生存质量评价（LCSS、QLQ—C30或QLQ—LC13）方面，患者自评和观察者评价均显示多西紫杉醇组优于支持治疗组。不同给药方案（3周给药和1周给药）的Meta分析结果可以看出不同给药方案在疾病控制率、反应率及1年生存率方面没有统计学差异（P〉0．05）；在嗜中性白细胞减少症、白细胞减少症的发生率上，1周给药组发生率均低于3周给药组（P〈0．01）；在非血液学不良反应如虚弱、恶心／呕吐的发生率上，不同给药方案没有统计学差异（P〉0．5）。结论多西紫杉醇可以认为是在晚期非小细胞肺癌的二线治疗中疗效确切的药物；不同的多西紫杉醇给药方案（3周vs1周），在疗效方面差异不明显，在不良反应发生率上略有差异，因此，在发生严重血液学不良反应的情况下，可以用1周给药代替3周给药进行治     

三种含铂化疗方案治疗晚期非小细胞肺癌的临床观察

目的 观察三种抗癌药(长春瑞滨、吉西他滨和多西紫杉醇)联合顺铂治疗晚期非小细胞肺癌(NSCLC)的近期疗效及毒性反应.方法 经病理组织学或细胞学证实的70例晚期NSCLC患者,随机按治疗方法 分为3组化疗,长春瑞滨联合顺铂(NP)组24例,吉西他滨联合顺铂(GP)组25例,多西紫杉醇联合顺铂(TP)组21例,3组患者资料具备可比性,3组患者采用对应药物进行治疗,均以21d为一周期,连续应用两周期后评价疗效及不良反应.结果 NP组总有效率29.2%(7/24),GP组总有效率40.0%(10/25),TP组总有效率33.3%(7/21),3组方案总有效率比较无统计学差异(P＞0.05);毒性反应方面,3组均以骨髓抑制为主,白细胞下降及贫血发生率相近.NP组Ⅰ～Ⅱ度静脉炎(14.6%)较其他两组多,GP组Ⅲ～Ⅳ度血小板降低(16%)较其他两组严重,TP组Ⅰ～Ⅱ度外周神经毒性(38.1%)较其他两组多.结论 用于晚期NSCLC一线化疗,NP、GP、TP三种方案近期疗效相似,但毒性存在差异,故应根据患者个体情况进行选择.     

顺铂联合多西他赛或吉西他滨治疗晚期非小细胞肺癌的临床对照研究

目的：比较多西他赛联合顺铂与吉西他滨联合顺铂治疗晚期非小细胞肺癌（NSCLC）的近期临床疗效和不良反应。方法：将84例晚期非小细胞肺癌患者随机分为多西他赛和顺铂组（DC组）42例及吉西他滨和顺铂组（GC组）42例。同一方案治疗2个周期评估近期疗效及不良反应。结果：评价入组的84例患者的近期疗效,DC组和GC组有效率分别为45.2%和40.5%,两组之间有效率差异无统计学意义（P〉0.05）。毒副反应主要为骨髓抑制和消化道反应。结论：多西他赛加顺铂与吉西他滨加顺铂方案治疗晚期非小细胞肺癌均具有较好的临床疗效且两者的疗效相似,不良反应可以耐受,可以用于临床一线治疗。     

Multifunctional silica nanoparticles for targeted delivery of hydrophobic imaging and therapeutic agents

This article reports the development of a multifunctional silica nanoparticle system for targeted delivery of hydrophobic imaging and therapeutic agents. Normally, silica nanoparticles have been widely used to deliver hydrophilic drugs such as doxorubicin while difficult to carry hydrophobic drugs. A strategy for loading hydrophobic drugs onto silica nanoparticles via covalent attachment was developed in this study as a universal strategy to solve this problem. Docetaxel, one of the most potent therapeutics for cancer treatment is selected as a model hydrophobic drug and quantum dots (QDs) are used as a model imaging agent. Such a multifunctional delivery system possesses high drug loading capacity, controlled drug release behavior and stable drug reservation. A mixed layer of polyethylene glycol conjugated phospholipids is formed on the nanoparticle surface to further enhance the biocompatibility and cell fusion capability of the delivery system. Folic acid as ligand is then conjugated onto the surface layer for targeting. Such a multifunctional system for targeting, imaging and therapy is characterized and evaluated in vitro. Fluorescent confocal microscopy is used to monitor the cellular uptake by specific cancer cells. Cytotoxicity studies are conducted by using MTT assay.     

Bivalent sequential binding of docetaxel to methyl-β-cyclodextrin

New docetaxel (Dtx) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility (up to 9.98 mg mL⁻¹) were obtained from phase solubility diagrams. γ-CD and SBE-β-CD offered only poor solubility enhancements while considerable increases in apparent solubility were obtained with Me-β-CD (20%, w/w) and HP-β-CD (40%, w/w) (9.98 mg mL⁻¹ and 7.43 mg mL⁻¹, respectively). The complexation mechanism between Dtx and Me-β-CD was investigated by circular dichroism spectrometry, two-dimensional ¹H NMR (NOESY) in D₂O, isothermal titration calorimetry (ITC) and molecular docking calculations. Circular dichroism and NOESY confirmed the existence of non-covalent interactions between Dtx and Me-β-CD and suggested that the tert-butyl group (C₆-C₉) and two aromatic groups (C₂₄-C₂₉ and C₃₀-C₃₅) of Dtx interacted with the Me-β-CD molecules. The combination of ITC results to molecular docking calculations led to the identification of an unconventional sequential binding mechanism between Me-β-CD and Dtx. In this sequential binding, a Me-β-CD molecule first interacted with both tert-butyl and C₃₀-C₃₅ aromatic groups (K₁: 744 M⁻¹). Then a second Me-β-CD molecule interacted with the C₂₄-C₂₉ aromatic group (K₂: 202 M⁻¹). The entropy of the first interaction was positive, whereas a negative value of entropy was found for the second interaction. The opposite behavior observed for these two sites was explained by differences in the hydrophobic contact surface and functional group flexibility.     

培美曲塞与DP方案在非小细胞肺癌二线治疗中临床疗效观察

目的 比较DP 方案与培美曲塞在晚期非小细胞肺癌(NSCLC) 治疗中的近期疗效和毒副反应.方法 NSCLC 患者27例.分别接受DP方案和培美曲塞两种方案的治疗,其中培美曲塞组13例,DP组14例,治疗2个周期后分别评价疗效和毒副反应.结果 有效率培美曲塞组为23.1%,DP组为28.6%,差异无统计学意义(P>0....